Due to the established link between tissue function, metabolism, and tissue perfusion, hemodynamic imaging with magnetic resonance (MR) can offer a unique window into the function of the pathophysiologically altered brain. The goal of the present research proposal is the development and evaluation of quantitative MR based methods for measurement of regional cerebral blood flow (CBF) and blood volume (CBV) in the specific setting of acute focal cerebral ischemia. This renewal remains focused on the refinement and extension of MR imaging techniques based on susceptibility contrast measurements that are opimally sensitive in detecting and characterizing regional brain microscopic hemodynamics using kinetic modeling of injected contrast agents. In the proposed research, we combine novel technical developments with important biological studies that take specific advantage of our new capabilities. We will focus on cerebrovascular insult, an area where the development of such tools could have major clinical impact. Technical development will focus first on extending our understanding of the dynamic measurement of cerebral blood volume (CBV) under low cerebral blood flow (CBF) conditions. We will use a novel two contrast agent protocol to study the differences between equilibrium and bolus CBV determinations, following this, extensive studies of the natural history of CBF-CBV mismatches after permanent and transient ischemia in the rat will provide a physiological framework for the study of hemodynamics in stroke patients. In these animals, we will utilize both filament and a new thromboembolic stroke model, and study the influence of t-PA reperfusion on hemodynamic status. Second, based on encouraging preliminary data in the human, we purpose to optimize and validate a new method in extract CBF from bolus measurements. Our approach to measurement of CBF in humans is by necessity more complex than in our animal studies, and focuses on the evaluation of the peak of the tissue residue function to directly measure flow. The ability to produce physiologically interpretable images of both CBV and CBF noninvasively over extended periods of time, will then be used to evaluate the natural history of cerebrovascular hemodynamics following ischemic stroke in humans. Our overall hypothesis is that functional MRI is capable of documenting evidence of perturbed CBV, CBF and their ratio, MTT, and that these hemodynamic parameters can identify tissue at risk for eventual infarction.